scholarly journals Inhibition of Human Immunodeficiency Virus Type 1 Entry in Cells Expressing gp41-Derived Peptides

2004 ◽  
Vol 78 (2) ◽  
pp. 568-575 ◽  
Author(s):  
Marc Egelhofer ◽  
Gunda Brandenburg ◽  
Holger Martinius ◽  
Patricia Schult-Dietrich ◽  
Gregory Melikyan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Heptad Repeat ◽  
Therapeutic Approaches ◽  
Transmembrane Glycoprotein ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1 ◽  
Maximal Expression

ABSTRACT As the limitations of antiretroviral drug therapy, such as toxicity and resistance, become evident, interest in alternative therapeutic approaches for human immunodeficiency virus (HIV) infection is growing. We developed the first gene therapeutic strategy targeting entry of a broad range of HIV type 1 (HIV-1) variants. Infection was inhibited at the level of membrane fusion by retroviral expression of a membrane-anchored peptide derived from the second heptad repeat of the HIV-1 gp41 transmembrane glycoprotein. To achieve maximal expression and antiviral activity, the peptide itself, the scaffold for presentation of the peptide on the cell surface, and the retroviral vector backbone were optimized. This optimized construct effectively inhibited virus replication in cell lines and primary blood lymphocytes. The membrane-anchored C-peptide was also shown to bind to free gp41 N peptides, suggesting that membrane-anchored antiviral C peptides have a mode of action similar to that of free gp41 C peptides. Preclinical toxicity and efficacy studies of this antiviral vector have been completed, and clinical trials are in preparation.

scholarly journals Membrane-Anchored Peptide Inhibits Human Immunodeficiency Virus Entry

2001 ◽  
Vol 75 (6) ◽  
pp. 3038-3042 ◽  
Author(s):  
Markus Hildinger ◽  
Matthias T. Dittmar ◽  
Patricia Schult-Dietrich ◽  
Boris Fehse ◽  
Barbara S. Schnierle ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Helper ◽  
Immunodeficiency Virus ◽  
Retrovirus Vector ◽  
Human Immunodeficiency Virus Entry ◽  
Hiv Type 1 ◽  
Heptad Repeats ◽  
Hiv 1 ◽  
Gp41 Envelope

ABSTRACT Peptides derived from the heptad repeats of human immunodeficiency virus (HIV) gp41 envelope glycoprotein, such as T20, can efficiently inhibit HIV type 1 (HIV-1) entry. In this study, replication of HIV-1 was inhibited more than 100-fold in a T-helper cell line transduced with a retrovirus vector expressing membrane-anchored T20 on the cell surface. Inhibition was independent of coreceptor usage.

scholarly journals Effect of Human Immunodeficiency Virus (HIV) Type 1 Viral Genotype on Mother‐to‐Child Transmission of HIV‐1

2000 ◽  
Vol 181 (2) ◽  
pp. 746-749 ◽  
Author(s):  
Melanie C. M. Murray ◽  
Joanne E. Embree ◽  
Sue G. Ramdahin ◽  
Aggrey O. Anzala ◽  
Simon Njenga ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mother To Child Transmission ◽  
Viral Genotype ◽  
Child Transmission ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Mother To Child ◽  
Hiv 1

Cell-Mediated Immune Response to Human Immunodeficiency Virus (HIV) Type 1 in Seronegative Homosexual Men with Recent Sexual Exposure to HIV-1

1992 ◽  
Vol 165 (6) ◽  
pp. 1012-1019 ◽  
Author(s):  
Mario Clerici ◽  
Janis V. Giorgi ◽  
Chen-Cheng Chou ◽  
Vaheideh K. Gudeman ◽  
Jerome A. Zack ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
Homosexual Men ◽  
Cell Mediated Immune Response ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

scholarly journals Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Human Monoclonal Antibody That Recognizes a Novel Conformational Epitope on gp41 and Lacks Reactivity against Self-Antigens

2008 ◽  
Vol 82 (14) ◽  
pp. 6869-6879 ◽  
Author(s):  
Mei-Yun Zhang ◽  
Bang K. Vu ◽  
Anil Choudhary ◽  
Hong Lu ◽  
Michael Humbert ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Immunodeficiency Virus ◽  
Conformational Epitope ◽  
Heptad Repeat ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Antibody ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Self Antigens

ABSTRACT Broadly cross-reactive human immunodeficiency virus (HIV)-neutralizing antibodies are infrequently elicited in infected humans. The two best-characterized gp41-specific cross-reactive neutralizing human monoclonal antibodies, 4E10 and 2F5, target linear epitopes in the membrane-proximal external region (MPER) and bind to cardiolipin and several other autoantigens. It has been hypothesized that, because of such reactivity to self-antigens, elicitation of 2F5 and 4E10 and similar antibodies by vaccine immunogens based on the MPER could be affected by tolerance mechanisms. Here, we report the identification and characterization of a novel anti-gp41 monoclonal antibody, designated m44, which neutralized most of the 22 HIV type 1 (HIV-1) primary isolates from different clades tested in assays based on infection of peripheral blood mononuclear cells by replication-competent virus but did not bind to cardiolipin and phosphatidylserine in an enzyme-linked immunosorbent assay and a Biacore assay nor to any protein or DNA autoantigens tested in Luminex assays. m44 bound to membrane-associated HIV-1 envelope glycoproteins (Envs), to recombinant Envs lacking the transmembrane domain and cytoplasmic tail (gp140s), and to gp41 structures containing five-helix bundles and six-helix bundles, but not to N-heptad repeat trimers, suggesting that the C-heptad repeat is involved in m44 binding. In contrast to 2F5, 4E10, and Z13, m44 did not bind to any significant degree to denatured gp140 and linear peptides derived from gp41, suggesting a conformational nature of the epitope. This is the first report of a gp41-specific cross-reactive HIV-1-neutralizing human antibody that does not have detectable reactivity to autoantigens. Its novel conserved conformational epitope on gp41 could be helpful in the design of vaccine immunogens and as a target for therapeutics.

scholarly journals Persistence of Human Immunodeficiency Virus (HIV) Type 1 DNA in Peripheral Blood Despite Prolonged Suppression of Plasma HIV‐1 RNA in Children

2002 ◽  
Vol 185 (10) ◽  
pp. 1409-1416 ◽  
Author(s):  
Akihiko Saitoh ◽  
Karen Hsia ◽  
Terence Fenton ◽  
Christine A. Powell ◽  
Cindy Christopherson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

scholarly journals Human Immunodeficiency Virus Type 1 (HIV-1)-Induced GRO-α Production Stimulates HIV-1 Replication in Macrophages and T Lymphocytes

2001 ◽  
Vol 75 (13) ◽  
pp. 5812-5822 ◽  
Author(s):  
Brian R. Lane ◽  
Robert M. Strieter ◽  
Michael J. Coffey ◽  
David M. Markovitz
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Human Monocyte ◽  
Peripheral Blood Mononuclear ◽  
Chemokine Production ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Early Effects ◽  
Hiv 1

ABSTRACT We examined the early effects of infection by CCR5-using (R5 human immunodeficiency virus [HIV]) and CXCR4-using (X4 HIV) strains of HIV type 1 (HIV-1) on chemokine production by primary human monocyte-derived macrophages (MDM). While R5 HIV, but not X4 HIV, replicated in MDM, we found that the production of the C-X-C chemokine growth-regulated oncogene alpha (GRO-α) was markedly stimulated by X4 HIV and, to a much lesser extent, by R5 HIV. HIV-1 gp120 engagement of CXCR4 initiated the stimulation of GRO-α production, an effect blocked by antibodies to CXCR4. GRO-α then fed back and stimulated HIV-1 replication in both MDM and lymphocytes, and antibodies that neutralize GRO-α or CXCR2 (the receptor for GRO-α) markedly reduced viral replication in MDM and peripheral blood mononuclear cells. Therefore, activation of MDM by HIV-1 gp120 engagement of CXCR4 initiates an autocrine-paracrine loop that may be important in disease progression after the emergence of X4 HIV.

scholarly journals Identification of a Critical Motif for the Human Immunodeficiency Virus Type 1 (HIV-1) gp41 Core Structure: Implications for Designing Novel Anti-HIV Fusion Inhibitors

2008 ◽  
Vol 82 (13) ◽  
pp. 6349-6358 ◽  
Author(s):  
Yuxian He ◽  
Jianwei Cheng ◽  
Jingjing Li ◽  
Zhi Qi ◽  
Hong Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Core Structure ◽  
Heptad Repeat ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into the host cell involves a cascade of events and currently represents one of most attractive targets in the search for new antiviral drugs. The fusion-active gp41 core structure is a stable six-helix bundle (6-HB) folded by its trimeric N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). Peptides derived from the CHR region of HIV-1 gp41 are potent fusion inhibitors that target the NHR to block viral and cellular membrane fusion in a dominant negative fashion. However, all CHR peptides reported to date are derived primarily from residues 628 to 673 of gp41; little attention has been paid to the upstream sequence of the pocket binding domain (PBD) in the CHR. Here, we have identified a motif (621QIWNNMT627) located at the upstream region of the gp41 CHR, immediately adjacent to the PBD (628WMEWEREI635). Biophysical characterization demonstrated that this motif is critical for the stabilization of the gp41 6-HB core. The peptide CP621-652, containing the 621QIWNNMT627 motif, was able to interact with T21, a counterpart peptide derived from the NHR, to form a typical 6-HB structure with a high thermostability (thermal unfolding transition [T m ] value of 82°C). In contrast, the 6-HB formed by the peptides N36 and C34, which has been considered to be a core structure of the fusion-active gp41, had a T m of 64°C. Different from T-20 (brand name Fuseon), which is the first and only HIV-1 fusion inhibitor approved for clinical use, CP621-652 could efficiently block 6-HB formation in a dose-dependent manner. Significantly, CP621-652 had potent inhibitory activity against HIV-1-mediated cell-cell fusion and infection, especially against T-20- and C34-resistant virus. Therefore, our works provide important information for understanding the core structure of the fusion-active gp41 and for designing novel anti-HIV peptides.

scholarly journals Strong Human Immunodeficiency Virus (HIV)-Specific Cytotoxic T-Lymphocyte Activity in Sydney Blood Bank Cohort Patients Infected with nef-Defective HIV Type 1

1999 ◽  
Vol 73 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Wayne B. Dyer ◽  
Graham S. Ogg ◽  
Marie-Ange Demoitie ◽  
Xia Jin ◽  
Andrew F. Geczy ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Blood Bank ◽  
Specific Ctls ◽  
Sydney Blood Bank Cohort ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Proposals for the use of live attenuated human immunodeficiency virus (HIV) type 1 (HIV-1) as a vaccine candidate in humans have been based on the protection afforded by attenuated simian immunodeficiency virus in the macaque model. Although it is not yet known if this strategy could succeed in humans, a study of the Sydney Blood Bank Cohort (SBBC), infected with an attenuated HIV-1 quasispecies with natural nef and nef/long terminal repeat deletions for up to 17 years, could provide insights into the long-term immunological consequences of living with an attenuated HIV-1 infection. In this study, HIV-specific cytoxic T-lymphocyte (CTL) responses in an SBBC donor and six recipients were examined over a 3-year period with enzyme-linked immunospot, tetrameric complex binding, direct CTL lysis, and CTL precursor level techniques. Strong HIV-specific CTL responses were detected in four of seven patients, including one patient with an undetectable viral load. Two of seven patients had weak CTL responses, and in one recipient, no HIV-specific CTLs were detected. High levels of circulating effector and memory HIV-specific CTLs can be maintained for prolonged periods in these patients despite very low viral loads.

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